EP0275696A1 - Dérivés de la pipéridine - Google Patents

Dérivés de la pipéridine Download PDF

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Publication number
EP0275696A1
EP0275696A1 EP87311320A EP87311320A EP0275696A1 EP 0275696 A1 EP0275696 A1 EP 0275696A1 EP 87311320 A EP87311320 A EP 87311320A EP 87311320 A EP87311320 A EP 87311320A EP 0275696 A1 EP0275696 A1 EP 0275696A1
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EP
European Patent Office
Prior art keywords
piperidine
diastereoisomer
formula
compound
dichlorophenylacetyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP87311320A
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German (de)
English (en)
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EP0275696B1 (fr
Inventor
Vittorio Vecchietti
Antonio Giordani
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr L Zambeletti SpA
Original Assignee
Dr L Zambeletti SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB868630639A external-priority patent/GB8630639D0/en
Priority claimed from GB878720492A external-priority patent/GB8720492D0/en
Application filed by Dr L Zambeletti SpA filed Critical Dr L Zambeletti SpA
Publication of EP0275696A1 publication Critical patent/EP0275696A1/fr
Application granted granted Critical
Publication of EP0275696B1 publication Critical patent/EP0275696B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms

Definitions

  • This invention is concerned with novel piperidine derivatives, processes for their preparation, and their use in medicine, particularly as analgesics.
  • K-receptor agonists act as analgesics through interaction with Kappa opioid receptors.
  • European Published Application No. 232,612 discloses a group of piperidine derivatives which exhibit K-receptor agonism without the behavioural effects of morphine and morphine analogues, and which are thus of potential therapeutic utility as analgesics.
  • R.CO- is an acyl group containing a substituted or unsubstituted carbocyclic aromatic or heterocyclic aromatic group
  • R1 and R2 are independently hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 cycloalkyl, or C 1-12 cycloalkylalkyl groups or together form a C 2-6 polymethylene or C 2-6 alkylene group, optionally substituted with a hetero-atom, provided that R1 and R2 are not simultaneously hydrogen
  • Rx is C 1-6 alkyl preferably methyl or ethyl, or phenyl, or Rx together with R1 form a -(CH2)3- or -(CH2)4- group.
  • the term 'carbocyclic aromatic group' includes single or fused rings, having 6 to 12 carbon atoms
  • 'heterocyclic aromatic group' includes single or fused rings having 5 to 12 atoms, comprising up to four hetero-atoms in the or each ring, selected from oxygen, nitrogen and sulphur.
  • one or both single rings may be aromatic in character.
  • one of the rings is aromatic and the other is non-aromatic.
  • R1 and R2 are C 1-6 alkyl groups, examples are methyl, ethyl, propyl, butyl, pentyl or hexyl groups, preferably methyl.
  • Examples of C 1-6 alkenyl groups are 1- and 2- propenyl; an example of a C 1-6 cycloalkyl group is cyclopropyl, and an example of a C 1-12 cycloalkylalkyl group is cyclopropylmethyl.
  • R1 and R2 together form a polymethylene group
  • examples are propylene, butylene, pentylene or hexylene, preferably butylene.
  • hetero-atoms are oxygen and sulphur, particularly oxygen, and a suitable hetero-atom substituted polymethylene group is -CH2-CH2OCH2-CH2-.
  • the group R preferably has the formula (II) in which n is 0, 1 or 2, m is 0, 1 or 2, m ⁇ is 0, 1 or 2, provided m + m ⁇ ⁇ 2;
  • X is a direct bond, or O, S or NR5 in which R5 is hydrogen or C 1-6 alkyl;
  • Ar is a substituted or unsubstituted carbocyclic aromatic or heterocyclic aromatic group, each of R3 and R3 a is an electron withdrawing substituent, C 1-6 alkoxy, haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkenyl, C 1-6 haloalkynyl, aryl or halogen or, when m is 2 and m ⁇ is 0, two R3's form a C 3-6 polymethylene group; and R4 is hydrogen or C 1-6 alkyl.
  • R3 or R3 a are -NO2-, -CN, -CF3, -Cl, Br,-OCF3, -OCHF2, -OCF2CF2H, -OCCl2CF3, -COOR6, -CONR7R8, -SO3R9, -SO2NR10R11 and -COR12 in which each of R6 to R2 is independently hydrogen, C 1-6 alkyl, aryl or aralkyl. When two R3's are linked they may form a fused cyclopentyl or cyclohexyl ring.
  • Examles of R4 are methyl and ethyl, and preferably R4 is hydrogen.
  • Ar is phenyl and R3 or R3 a is preferably in the meta- and/or para- position.
  • R3 or R3 a is bromine, chlorine, -NO2 or -CF3, particularly in the meta- or para-position.
  • X is typically oxygen or a direct bond
  • n is typically 0 or 1.
  • the compounds of formula I or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula I or its salt or solvate.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition.
  • the additional ionic and solvent moieties must also be non-toxic.
  • Examples of a pharmaceutically acceptable salt of a compound of formula I include the acid addition salts with the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • conventional pharmaceutical acids for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • Examples of a pharmaceutically acceptable solvate of a compound of formula I include the hydrate.
  • the compounds of formula I have at least two asymmetric centres and therefore exist in more than one stereoisomeric form.
  • the invention extends to all such forms and to mixtures thereof, including racemates.
  • the present invention also provides a process for the preparation of a compound of formula I which comprises reacting a compound of formula (III) in which R1 ⁇ and R2 ⁇ are R1 and R2 as defined for formula (I) or a group or atom convertible to R1 and R2, and Rx is as defined for formula (I) with a compound of formula R ⁇ - -OH or an active derivative thereof, in which R ⁇ is R as defined for formula (I) or a group convertible to R, to form a compound of formula (Ia) and then performing one or more of the following steps:
  • Suitable active derivatives of R ⁇ - -OH are acid chlorides or acid anhydrides.
  • Another suitable derivative is a mixed anhydride formed between the acid and the alkyl chloroformate.
  • a compound of formula (Ia) may be converted to a compound of formula (I), or one compound of formula (I) may be converted to another compound of formula (I), by interconversion of suitable substituents.
  • certain compounds of formula (I) and (Ia) are useful intermediates in forming other compounds of the present invention.
  • R1 ⁇ and R2 ⁇ may be alkyl groups and converted to R1 ⁇ /R2 ⁇ hydrogen atoms by conventional amine dealkylation.
  • R1 ⁇ or R2 ⁇ is benzyl or substituted benzyl it may be converted to an R1 or R2 ⁇ hydrogen atom by catalytic hydrogenation or other method of reduction.
  • R1 ⁇ and R2 ⁇ as hydrogen atoms may be converted to R1 and R2 alkyl groups by conventional amine alkylation, or by acylation followed by reduction.
  • R1 ⁇ and R2 ⁇ are preferably R1 and R2 respectively.
  • R ⁇ - -OH is typically of the formula (IIa) in which R3 ⁇ is R3 (R3 a ) ⁇ is R3 a as defined for formula (II) or a group or atom convertible to R3 or R3 a , the other variables being as defined for formula (II).
  • R3 ⁇ or R3 a ⁇ is generally known in the art of aromatic chemistry.
  • R3 ⁇ is preferably R3, and R3 a ⁇ is preferably R3 a .
  • the compounds of formula I may be converted into their pharmaceutically acceptable acid addition salts by reaction with the appropriate organic or mineral acids.
  • Solvates of the compounds of formula I may be formed by crystallization or recrystallization from the appropriate solvent.
  • hydrates may be formed by crystallization or recrystallization from aqueous solutions, or solutions in organic solvents containing water.
  • salts or solvates of the compounds of formula I which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Accordingly such salts or solvates also form part of this invention.
  • the compounds of formula I exist in more than one stereoisomeric form and the processes of the invention produces mixtures thereof.
  • the individual isomers may be separated one from another by resolution using an optically active acid such as tartaric acid.
  • an asymmetric synthesis would offer a route to the individual form.
  • the compound of formula (III) may be prepared from a compound of formula (IV) by the reaction scheme shown: In this scheme, a compound of formula (IV) is treated with a secondary amine R ⁇ 1R ⁇ 2NH in the presence of a reducing hydride, such as Na CNBH3, to form a compound of formula (V). The latter is then reduced catalytically using hydrogen/PtO2 to form a compound of formula (III).
  • a reducing hydride such as Na CNBH3
  • the compound of formula (III) may also be prepared from a compound of formula (IV) by the following reaction scheme: In this scheme, a compound of formula (IV) is transformed into an oxime of formula (VI) by treatment with hydroxylamine, which is then reduced to the corresponding amine of formula (VII) by, for example, treatment with zinc powder in ethanolic ammonia.
  • the compound of formula (VII) may be transformed to the amine of formula (V) by standard alkylation methods, such as, for example, the Leuckart-Wallach reaction (using HCHO and HCOOH) or by reaction with formaldehyde and NaCNBH3.
  • the compounds of formula (IV) are either known compounds or can be made from known compounds by known methods.
  • the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance, particularly for use in treating pain.
  • the present invention further provides a pharamceutical composition
  • a pharamceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically accetpable carrier.
  • the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of pain.
  • Such a medicament, and a composition of this invention may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of pain.
  • the suitable dosage range for the compounds of the invention depends on the compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
  • the compound or composition of the invention may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient.
  • Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • compositions may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example starch, polyvinylpyrrolidone, sodium
  • Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
  • any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • the composition may also be in the form of an ingestible capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients.
  • compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring
  • compositions may be formulated, for example for rectal adminsitration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • a pharmaceutically acceptable liquid e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • the liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives.
  • Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi-dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.
  • the effective dose of compound depends on the particular compound employed, the condition of the patient and on the frequency and route of administration.
  • a unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.
  • the composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg.
  • the unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
  • the present invention also provides a method of treating pain in mammals, particularly in humans, which comprises administering an effective amount of a compound of formula (I), or pharmaceutically acceptable salt or solvate thereof, to a sufferer.
  • oily residue (gr 2.8) was chromatographed on 12 g. of silicagel,eluting with CH2Cl2 containing 2% to 10% methanol. 1.7g. of oily product were obtained,sufficiently pure for the subsequent step.
  • threo diastereoisomer obtained as above described was resolved into its enantiomers by the following procedure: 5.37 g. (0.0157 moles) of threo 1-(3,4-dichlorophenylacetyl)-2-(1-­dimethylaminoethyl) piperidine dissolved in ml 50 of dry acetone were added on stirring to a solution of 4 g. (0.016 moles) of (+) - camphor-10-sulfonic acid monohydrate dissolved in 100 ml of dry acetone; the precipitated salt was collected by suction fil­tration, washed with cold dry acetone and dried at 80°C; yield g. 2.2 m.p.
  • the amide of heading B) was reduced to amine with LiAlH4 in THF,by the standard method. 3.2 g. of crude product were obtained,sufficiently pure for the subsequent step.
  • Diastereoisomer B was obtained as an oil,and transformed into the hydrochloride by dissolving in acetone and acidifying with HCl/ether. The precipitated salt was crystallized from methanol. Yield g. 0.7 C22H26N2Cl2O.HCl. M.W. 441.823 M.P. 255-7°C
  • the diastereoisomer B was obtained from the mother liquors by fractional crystallisation as its hydrochloride.
  • the acidic solution was washed with ether and made alkaline by adding solid NaOH.
  • the oily material separated from the basic aqueous solution was extracted with ether, dried and evaporated to oily mixture of diastereosiomers. This was chromatographed on 100 g. of silicagel, eluting with hexane containing increasing amounts of Ethyl acetate.
  • the fast moving diastereoisomer A so obtained was dissolved in acetone and acidified with HCl dissolved in ether.
  • the pharmacological activity of the compounds of this invention is illustrated by various in vitro and in vivo models, using the following test procedures, in which the mouse tail flick test demonstrate analgesic activity.
  • mice Male Charles River mice, average weight 26g, are used. Selection is carried out before beginning of experiments: only mice whose reaction time is less than 8 sec are used. They are randomly distributed into groups of 10 and dosed with compounds under test, with positive and negative controls being included.
  • the analgesic activity of the test compound is expressed as the percent number of mice doubling the initial time within a group.
  • Radio receptor binding to ⁇ and K sites is performed on fresh guinea pig brain homogenate prepared according to Kosterlitz. (1981).
  • the pellet is then resuspended in the same buffer, incubated at 37°C for 45 min. and centrifuged again.
  • Enkephalin 3H [D-Ala2, MePhe4, Gly-ol5] Enkephalin (3H-DAGO), an enkephalin analogue that binds selectively to ⁇ receptor, is added to the biological substrate and incubated at 25°C for 40 min., filtered through Whatman GF-C and washed with ice-cold Tris-buffer.
  • the filters are then dryed, solubilized in Filtercount and the radioactivity monitored. Non specific binding is determined in the presence of 10 ⁇ 6M Naloxone.
  • the radioactivity bound to the filters is counted by liquid scintillation spectrophotometry.
  • MR 2266.500 nM is utilized to determine the saturable binding.
  • the equilibrium dissociation constant (K D ), the inhibition constant (Ki) and the maximum number of binding sites (B max) are determined from saturation curves and competition experiments (Hill 1910; Scatchard 1949; Cheng and Prusoff 1973; Gillan et al. 1980).
  • a concentration of radioligand near K D is used in the binding assays evaluating our compunds.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP87311320A 1986-12-22 1987-12-22 Dérivés de la pipéridine Expired - Lifetime EP0275696B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB868630639A GB8630639D0 (en) 1986-12-22 1986-12-22 Compounds
GB8630639 1986-12-22
GB878720492A GB8720492D0 (en) 1987-08-29 1987-08-29 Compounds
GB8720492 1987-08-29

Publications (2)

Publication Number Publication Date
EP0275696A1 true EP0275696A1 (fr) 1988-07-27
EP0275696B1 EP0275696B1 (fr) 1992-04-01

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EP87311320A Expired - Lifetime EP0275696B1 (fr) 1986-12-22 1987-12-22 Dérivés de la pipéridine

Country Status (9)

Country Link
US (1) US4879300A (fr)
EP (1) EP0275696B1 (fr)
JP (1) JPS6413070A (fr)
KR (1) KR890005052A (fr)
AU (1) AU603850B2 (fr)
DE (1) DE3777997D1 (fr)
DK (1) DK674487A (fr)
NZ (1) NZ223017A (fr)
PT (1) PT86427B (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0330461A2 (fr) * 1988-02-23 1989-08-30 Glaxo Group Limited Dérivés de pipéridine
EP0372694A2 (fr) * 1988-10-17 1990-06-13 SmithKline Beecham Farmaceutici S.p.A. Dérivés azacycliques à activité diurétique
EP0333315B1 (fr) * 1988-02-12 1991-06-12 Dr. Lo. Zambeletti S.p.A. Composés azacycliques, procédés pour leur préparation et leur application comme médicaments
EP0447704A1 (fr) * 1990-03-21 1991-09-25 Smithkline Beecham Farmaceutici S.p.A. Composés azacycliques N-acylés, procédés pour leur préparation et leur utilisation comme médicaments
WO1991017116A1 (fr) * 1990-04-28 1991-11-14 Dr. Lo. Zambeletti S.P.A. Nouvelles piperidines de 1-(2h-1-oxo-3,4-dihydronaphtyle-6)-acetyle, procede de preparation et utilisation therapeutique
WO1991017981A1 (fr) * 1990-05-24 1991-11-28 Dr. Lo. Zambeletti S.P.A. Derives azacycliques
US5109008A (en) * 1988-10-18 1992-04-28 Glaxo Group Limited Pharmaceutically useful furo[3,2-c]pyridines
US5114945A (en) * 1988-02-23 1992-05-19 Glaxo Group Limited Spiropiperidine derivatives
US5116842A (en) * 1989-05-18 1992-05-26 Glaxo Group Limited Chemical compounds
WO2002078744A1 (fr) * 2001-03-30 2002-10-10 Toray Industries, Inc. Remedes contre la psychonevrose

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2017932B3 (es) * 1985-12-23 1991-03-16 Dr Lo Zambeletti S P A Compuestos azaciclicos, procedimientos de su preparacion y su uso como farmacos.
ES2039242T3 (es) * 1986-09-02 1993-09-16 Dr. Lo. Zambeletti S.P.A. Un procedimiento para la preparacion de nuevos derivados de piperidina.
US5512567A (en) * 1988-08-24 1996-04-30 Sankyo Company, Limited Analgesic compounds, their preparation, and pharmaceutical compositions containing them
US5254556A (en) * 1988-11-07 1993-10-19 Janssen Pharmaceutica N.V. 3-piperidinyl-1,2-benzisoxazoles
GB8906792D0 (en) 1989-03-23 1989-05-10 Beecham Wuelfing Gmbh & Co Kg Treatment and compounds
GB8926560D0 (en) * 1989-11-24 1990-01-17 Zambeletti Spa L Pharmaceuticals
US5189046A (en) * 1990-08-14 1993-02-23 Nova Pharmaceutical Corporation Protein kinase C modulators
FR2705343B1 (fr) * 1993-05-17 1995-07-21 Fournier Ind & Sante Dérivés de beta,beta-diméthyl-4-pipéridineéthanamine, leur procédé de préparation et leur utilisation en thérapeutique.
KR100428799B1 (ko) * 2001-09-04 2004-04-28 엘지전자 주식회사 폴링방식에 의한 하드웨어 인터럽트 처리 방법
WO2005032479A2 (fr) 2003-10-01 2005-04-14 Unviversity Of Florida Research Foundation, Inc. Compositions et methodes d'inhibition selective des recepteurs nicotiniques de l'acetylcholine

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Cited By (14)

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Publication number Priority date Publication date Assignee Title
EP0333315B1 (fr) * 1988-02-12 1991-06-12 Dr. Lo. Zambeletti S.p.A. Composés azacycliques, procédés pour leur préparation et leur application comme médicaments
US5114945A (en) * 1988-02-23 1992-05-19 Glaxo Group Limited Spiropiperidine derivatives
EP0330461A3 (fr) * 1988-02-23 1990-10-17 Glaxo Group Limited Dérivés de pipéridine
EP0330461A2 (fr) * 1988-02-23 1989-08-30 Glaxo Group Limited Dérivés de pipéridine
EP0372694A2 (fr) * 1988-10-17 1990-06-13 SmithKline Beecham Farmaceutici S.p.A. Dérivés azacycliques à activité diurétique
EP0372694A3 (fr) * 1988-10-17 1991-11-21 SmithKline Beecham Farmaceutici S.p.A. Dérivés azacycliques à activité diurétique
US5109008A (en) * 1988-10-18 1992-04-28 Glaxo Group Limited Pharmaceutically useful furo[3,2-c]pyridines
US5116842A (en) * 1989-05-18 1992-05-26 Glaxo Group Limited Chemical compounds
EP0447704A1 (fr) * 1990-03-21 1991-09-25 Smithkline Beecham Farmaceutici S.p.A. Composés azacycliques N-acylés, procédés pour leur préparation et leur utilisation comme médicaments
WO1991017116A1 (fr) * 1990-04-28 1991-11-14 Dr. Lo. Zambeletti S.P.A. Nouvelles piperidines de 1-(2h-1-oxo-3,4-dihydronaphtyle-6)-acetyle, procede de preparation et utilisation therapeutique
US5428042A (en) * 1990-04-28 1995-06-27 Dr Lo Zambeletti S.P.A. 1-(2H-1-oxo-3,4-dihydronaphtyl-6-yl)-acetyl-piperidines as kappa agonists
WO1991017981A1 (fr) * 1990-05-24 1991-11-28 Dr. Lo. Zambeletti S.P.A. Derives azacycliques
WO2002078744A1 (fr) * 2001-03-30 2002-10-10 Toray Industries, Inc. Remedes contre la psychonevrose
US8338442B2 (en) 2001-03-30 2012-12-25 Toray Industries, Inc. Remedies for psychoneurosis

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JPS6413070A (en) 1989-01-17
NZ223017A (en) 1990-07-26
AU603850B2 (en) 1990-11-29
DK674487A (da) 1988-06-23
AU8286787A (en) 1988-06-23
KR890005052A (ko) 1989-05-11
DK674487D0 (da) 1987-12-21
EP0275696B1 (fr) 1992-04-01
PT86427A (en) 1988-01-01
US4879300A (en) 1989-11-07
DE3777997D1 (de) 1992-05-07
PT86427B (pt) 1990-11-20

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